CORRESPONDENCE 2. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178: 218–224. 3. Gupta S, Hartley R, Khan UT, Singapuri A, Hargadon B, Monteiro W, Pavord ID, Sousa AR, Marshall RP, Subramanian D, et al. Quantitative computed tomography-derived clusters: redefining airway remodeling in asthmatic patients. J Allergy Clin Immunol 2014; 133:729–738, e18. 4. Gupta S, Raj V, Castro M, Brightling CE. Imaging in severe asthma. Eur Respir Monogr 2011;51:160–181. 5. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease. Lancet 2008;372: 1107–1119. 6. Gupta S, Hartley R, Khan UT, Entwisle JJ, Raj V, Brightling CE. Asthma phenotypes based on quantitative computed tomography analysis of proximal and distal airway remodeling [abstract]. Presented at the Radiological Society of North America 2012 Scientific Assembly and Annual Meeting. November 25–30, 2012, Chicago, IL. 7. Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, Marshall RP, Bradding P, Green RH, Wardlaw AJ, et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360:973–984. 8. Niimi A, Matsumoto H, Amitani R, Nakano Y, Sakai H, Takemura M, Ueda T, Chin K, Itoh H, Ingenito EP, et al. Effect of short-term treatment with inhaled corticosteroid on airway wall thickening in asthma. Am J Med 2004;116:725–731. 9. Lee YM, Park JS, Hwang JH, Park SW, Uh ST, Kim YH, Park CS. High-resolution CT findings in patients with near-fatal asthma: comparison of patients with mild-to-severe asthma and normal control subjects and changes in airway abnormalities following steroid treatment. Chest 2004;126: 1840–1848. 10. Wang K, Liu CT, Wu YH, Feng YL, Bai HL, Ma ES, Wen FQ. Effects of formoterol-budesonide on airway remodeling in patients with moderate asthma. Acta Pharmacol Sin 2011;32: 126–132. 11. Hoshino M, Ohtawa J. Effects of adding omalizumab, an antiimmunoglobulin E antibody, on airway wall thickening in asthma. Respiration 2012;83:520–528. 12. Brillet PY, Attali V, Nachbaur G, Capderou A, Becquemin MH, Beigelman-Aubry C, Fetita CI, Similowski T, Zelter M, Grenier PA. Multidetector row computed tomography to assess changes in airways linked to asthma control. Respiration 2011;81: 461–468. 13. Matsumoto H, Niimi A, Takemura M, Ueda T, Yamaguchi M, Matsuoka H, Jinnai M, Takeda T, Otsuka K, Oguma T, et al. Long-term changes in airway-wall thickness on computed tomography in asthmatic patients. J Investig Allergol Clin Immunol 2011;21: 113–119. 14. Witt CA, Sheshadri A, Carlstrom L, Tarsi J, Kozlowski J, Wilson B, Gierada DS, Hoffman E, Fain SB, Cook-Granroth J, et al.; NHLBI Severe Asthma Research Program (SARP). Longitudinal changes in airway remodeling and air trapping in severe asthma. Acad Radiol 2014;21:986–993. 15. Williamson JP, McLaughlin RA, Noffsinger WJ, James AL, Baker VA, Curatolo A, Armstrong JJ, Regli A, Shepherd KL, Marks GB, et al. Elastic properties of the central airways in obstructive lung diseases measured using anatomical optical coherence tomography. Am J Respir Crit Care Med 2011;183: 612–619. 16. Macklem PT. A theoretical analysis of the effect of airway smooth muscle load on airway narrowing. Am J Respir Crit Care Med 1996; 153:83–89. 17. Lambert RK, Pare´ PD. Lung parenchymal shear modulus, airway wall remodeling, and bronchial hyperresponsiveness. J Appl Physiol (1985) 1997;83:140–147.
Copyright © 2015 by the American Thoracic Society
110
Intraindividual Response to Treatment with Pirfenidone in Idiopathic Pulmonary Fibrosis To the Editor: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with an extremely poor prognosis (1–4). Pirfenidone, an orally available, antifibrotic drug, has recently been shown to slow down the loss of FVC and to improve survival in patients with IPF (5–7). However, there is currently no knowledge with regard to intraindividual changes in response to this treatment. We conducted a retrospective analysis of treatment-elicited changes in lung function and gas exchange in two independent IPF cohorts in Giessen, Germany (n = 84), and Turin, Italy (n = 113). In addition, FVC data from 100 consecutive patients with IPF from the prepirfenidone era were used to validate the methodological approach (control group). This letter summarizes our key observations. Diagnosis of IPF was made in accordance with the guidelines (2); baseline characteristics of the patients are summarized in Table 1. All patients in whom treatment with pirfenidone had been initiated between July 2010 and August 2013 and who received at least a single dose of pirfenidone were included. Next to FVC, total lung capacity (TLC), diffusing capacity of carbon monoxide (DLCO), and oxygenation after Horowitz, adverse effects, complaints, and concomitant therapies, including bronchodilator use, were recorded. Some of the results of these studies have been previously reported in the form of an abstract (8). In the control cohort, the FVC slope did not change in response to a random setting of baseline (generalized linear method [GLM], SAS 9.3; see online supplement). In contrast, the annual decline in FVC, being 27.0 6 1.8% or 248.1 6 199.3 ml per year before treatment in the combined IPF cohorts (n = 197), was significantly (P , 0.0001) decreased under pirfenidone (12.7 6 3.6% or 151.4 6 351.4 ml per year; see online supplement), as was TLC (P = 0.0015), DLCO (P , 0.0001) and oxygenation after Horowitz (P , 0.0001; see online supplement). In a more restricted approach (per protocol analysis, n = 147), we included only patients with more than three pulmonary function tests before/after treatment, an observation period of more than 6 months before pirfenidone, and an intraindividual FVC slope calculation (GLM, SAS 9.3). In this cohort, the overall response was comparable to the global population analysis. A striking therapeutic effect of pirfenidone was encountered especially in progressive IPF: Whereas stable patients (n = 71; decline of FVC < 10% per annum) remained stable under therapy, the progressive patients (n = 76; decline of FVC . 10% per annum) did profit substantially from pirfenidone, resulting even in an improvement of FVC (292 6 185 ml per annum; Figure 1, left). Supported by the German Center for Lung Research (Deutsches Zentrum fur ¨ Lungenforschung). In addition, a first draft of this manuscript was provided by nspm ltd, Meggen, Switzerland, with financial support from InterMune Deutschland GmbH. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
CORRESPONDENCE Table 1. Demographics, Diagnosis, and Treatment Information
Parameter Age, yr Body mass index, kg/m2 Weight, kg Sex, n (%) Male Smoking status at baseline, n (%) Never-smoker Ex-smoker Current smoker Pack-years, yr Idiopathic pulmonary fibrosis comedication, n (%) Corticosteroids NAC Corticosteroids/NAC None Bronchodilators Idiopathic pulmonary fibrosis diagnosis surgical lung biopsy, n (%) Lung function at baseline FVC, % predicted FVC, L DLCO, % predicted Time until diagnosis, mo Time between diagnosis and pirfenidone initiation, mo Duration of pirfenidone treatment, mo
Cohort Turin (N = 113)
Cohort Giessen (N = 84)
Total (N = 197)
71.5 6 0.6 28.2 6 0.5 n/a
67.6 6 1.0 27.3 6 0.5 81.7 6 1.7
69.8 6 0.6 27.7 6 0.4
74 (65.5)
66 (78.6)
140 (71.0)
Turin vs. Giessen (P Value) 0.001 0.217
Control Group, No Pirfenidone (N = 100) 63.3 6 1.6 n/a n/a
0.057 72 (72.0) 0.031
38 (33.6) 75 (66.4) 0 (0.0) 30.6 6 2.7 8 6 16 83 22 31
(7.0) (5.3) (14.2) (73.5) (26.2) (27.4)
19 (22.6) 62 (73.8) 3 (3.6) 25.7 6 2.7 5 39 18 22 24 27
(6.0) (46.4) (21.4) (26.2) (21.2) (32.1)
66.6 6 19.1 2.2 6 0.8 41.6 6 14.0 21.9 6 3.0 54.5 6 4.2
63.3 6 18.5 2.5 6 0.8 38.4 6 18.9 24.9 6 6.8 41.15 6 4.9
10.2 6 5.5
10.5 6 9.0
57 (28.9) 137 (69.6) 3 (1.5) 28.2 6 1.9 13 46 35 103 46 58
(6.6) (23.3) (17.8) (52.3) (23.3) (29.4)
65.0 6 18.8 2.3 6 0.8 39.8 6 17.0 23.0 6 3.1 48.5 6 4.23 10.32 6 7.2
0.170 ,0.001
43 (43.0) 57 (57.0) 0 (0.0) 24.1 6 4 n/a
0.496 0.528
34 (34.0)
0.741 0.345 0.029 0.016 0.04
n/a n/a
0.541
Definition of abbreviations: DLCO = diffusing capacity of carbon monoxide; NAC = N-acetylcysteine. Data are mean 6 SEM unless otherwise indicated.
Finally, in an individualized analysis, we also applied the GLM analysis to the single per protocol patients for the posttreatment period (n = 97) and analyzed the intraindividual FVC data set (slope prior/post treatment) in a four-field matrix representing principle treatment scenarios: progressive prior and after therapy, progressive prior and stable after therapy, stable prior and stable after therapy, and finally, stable prior and progressive after therapy (cut-off value: FVC decline of more than 10% and also of more than 5% per annum). As evident from Figure 1 (right), the vast majority of cases were placed within the upper fields, indicating stable disease after treatment. When applying the 10% criterion, 79.3% of the patients in a progressive state before therapy were stabilized under pirfenidone treatment and were localized in the upper fields. In reverse, a minor, but not negligible, fraction of patients (20.6%) experienced disease progression when receiving pirfenidone therapy. This was similar when applying the 5% annual decline criterion. To our understanding, our data expand the current knowledge. First, in contrast to previous randomized controlled trials (9, 10), our global analysis even showed a slight increase in FVC after initiation of pirfenidone. This may be primarily based on differences in baseline characteristics, data analysis, extraction, and replacement policies; in our study, we did not impute missing values for those 30.5% of all patients stopping treatment with pirfenidone at some time during the Correspondence
observation period, nor did we set FVC as 0 in case a subject died (as had been done previously). Our patients were also older and more advanced compared with patients in previous randomized controlled trials. Of the patients in our trial, 23.4% were treated with bronchodilators before the onset of pirfenidone treatment, and no patient received pirfenidone along with bronchodilators. In line with such reasoning, the addition of age, use of bronchodilators, and sex did not improve the fit of the GLM model in the study and the control cohort. Second, an intraindividual, annual FVC decline greater than 10%, alternatively also greater than 5%, was used for stratification, as a decline of 5–10% or more is accepted as clinically meaningful (11, 12). Employing this approach, patients with a clear progression showed an even more favorable course under pirfenidone and actually improved. Such behavior reminds us of the treatment effect of imatinib in patients with pulmonary arterial hypertension, in whom the highest treatment effect was encountered in the subgroup of patients with the highest pulmonary vascular resistance values and, hence, the most active vascular remodeling processes (13). One may speculate that matrix deposition and dissolution take place at a much higher pace in progressive IPF. Under such conditions, blockade or a reduction of matrix production and deposition may actually result in matrix removal, provided abundant 111
CORRESPONDENCE trend FVC (yearly change) >0.3
2.0
0.1
1.8 p=0.0715
post
FVC/FVCtime=0
1.6 1.4
−0.05 −0.1
1.2 1.0 −0.3
0.8 0.6 0.4
Copyright © 2015 by the American Thoracic Society
110
Intraindividual Response to Treatment with Pirfenidone in Idiopathic Pulmonary Fibrosis To the Editor: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with an extremely poor prognosis (1–4). Pirfenidone, an orally available, antifibrotic drug, has recently been shown to slow down the loss of FVC and to improve survival in patients with IPF (5–7). However, there is currently no knowledge with regard to intraindividual changes in response to this treatment. We conducted a retrospective analysis of treatment-elicited changes in lung function and gas exchange in two independent IPF cohorts in Giessen, Germany (n = 84), and Turin, Italy (n = 113). In addition, FVC data from 100 consecutive patients with IPF from the prepirfenidone era were used to validate the methodological approach (control group). This letter summarizes our key observations. Diagnosis of IPF was made in accordance with the guidelines (2); baseline characteristics of the patients are summarized in Table 1. All patients in whom treatment with pirfenidone had been initiated between July 2010 and August 2013 and who received at least a single dose of pirfenidone were included. Next to FVC, total lung capacity (TLC), diffusing capacity of carbon monoxide (DLCO), and oxygenation after Horowitz, adverse effects, complaints, and concomitant therapies, including bronchodilator use, were recorded. Some of the results of these studies have been previously reported in the form of an abstract (8). In the control cohort, the FVC slope did not change in response to a random setting of baseline (generalized linear method [GLM], SAS 9.3; see online supplement). In contrast, the annual decline in FVC, being 27.0 6 1.8% or 248.1 6 199.3 ml per year before treatment in the combined IPF cohorts (n = 197), was significantly (P , 0.0001) decreased under pirfenidone (12.7 6 3.6% or 151.4 6 351.4 ml per year; see online supplement), as was TLC (P = 0.0015), DLCO (P , 0.0001) and oxygenation after Horowitz (P , 0.0001; see online supplement). In a more restricted approach (per protocol analysis, n = 147), we included only patients with more than three pulmonary function tests before/after treatment, an observation period of more than 6 months before pirfenidone, and an intraindividual FVC slope calculation (GLM, SAS 9.3). In this cohort, the overall response was comparable to the global population analysis. A striking therapeutic effect of pirfenidone was encountered especially in progressive IPF: Whereas stable patients (n = 71; decline of FVC < 10% per annum) remained stable under therapy, the progressive patients (n = 76; decline of FVC . 10% per annum) did profit substantially from pirfenidone, resulting even in an improvement of FVC (292 6 185 ml per annum; Figure 1, left). Supported by the German Center for Lung Research (Deutsches Zentrum fur ¨ Lungenforschung). In addition, a first draft of this manuscript was provided by nspm ltd, Meggen, Switzerland, with financial support from InterMune Deutschland GmbH. This letter has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
American Journal of Respiratory and Critical Care Medicine Volume 191 Number 1 | January 1 2015
CORRESPONDENCE Table 1. Demographics, Diagnosis, and Treatment Information
Parameter Age, yr Body mass index, kg/m2 Weight, kg Sex, n (%) Male Smoking status at baseline, n (%) Never-smoker Ex-smoker Current smoker Pack-years, yr Idiopathic pulmonary fibrosis comedication, n (%) Corticosteroids NAC Corticosteroids/NAC None Bronchodilators Idiopathic pulmonary fibrosis diagnosis surgical lung biopsy, n (%) Lung function at baseline FVC, % predicted FVC, L DLCO, % predicted Time until diagnosis, mo Time between diagnosis and pirfenidone initiation, mo Duration of pirfenidone treatment, mo
Cohort Turin (N = 113)
Cohort Giessen (N = 84)
Total (N = 197)
71.5 6 0.6 28.2 6 0.5 n/a
67.6 6 1.0 27.3 6 0.5 81.7 6 1.7
69.8 6 0.6 27.7 6 0.4
74 (65.5)
66 (78.6)
140 (71.0)
Turin vs. Giessen (P Value) 0.001 0.217
Control Group, No Pirfenidone (N = 100) 63.3 6 1.6 n/a n/a
0.057 72 (72.0) 0.031
38 (33.6) 75 (66.4) 0 (0.0) 30.6 6 2.7 8 6 16 83 22 31
(7.0) (5.3) (14.2) (73.5) (26.2) (27.4)
19 (22.6) 62 (73.8) 3 (3.6) 25.7 6 2.7 5 39 18 22 24 27
(6.0) (46.4) (21.4) (26.2) (21.2) (32.1)
66.6 6 19.1 2.2 6 0.8 41.6 6 14.0 21.9 6 3.0 54.5 6 4.2
63.3 6 18.5 2.5 6 0.8 38.4 6 18.9 24.9 6 6.8 41.15 6 4.9
10.2 6 5.5
10.5 6 9.0
57 (28.9) 137 (69.6) 3 (1.5) 28.2 6 1.9 13 46 35 103 46 58
(6.6) (23.3) (17.8) (52.3) (23.3) (29.4)
65.0 6 18.8 2.3 6 0.8 39.8 6 17.0 23.0 6 3.1 48.5 6 4.23 10.32 6 7.2
0.170 ,0.001
43 (43.0) 57 (57.0) 0 (0.0) 24.1 6 4 n/a
0.496 0.528
34 (34.0)
0.741 0.345 0.029 0.016 0.04
n/a n/a
0.541
Definition of abbreviations: DLCO = diffusing capacity of carbon monoxide; NAC = N-acetylcysteine. Data are mean 6 SEM unless otherwise indicated.
Finally, in an individualized analysis, we also applied the GLM analysis to the single per protocol patients for the posttreatment period (n = 97) and analyzed the intraindividual FVC data set (slope prior/post treatment) in a four-field matrix representing principle treatment scenarios: progressive prior and after therapy, progressive prior and stable after therapy, stable prior and stable after therapy, and finally, stable prior and progressive after therapy (cut-off value: FVC decline of more than 10% and also of more than 5% per annum). As evident from Figure 1 (right), the vast majority of cases were placed within the upper fields, indicating stable disease after treatment. When applying the 10% criterion, 79.3% of the patients in a progressive state before therapy were stabilized under pirfenidone treatment and were localized in the upper fields. In reverse, a minor, but not negligible, fraction of patients (20.6%) experienced disease progression when receiving pirfenidone therapy. This was similar when applying the 5% annual decline criterion. To our understanding, our data expand the current knowledge. First, in contrast to previous randomized controlled trials (9, 10), our global analysis even showed a slight increase in FVC after initiation of pirfenidone. This may be primarily based on differences in baseline characteristics, data analysis, extraction, and replacement policies; in our study, we did not impute missing values for those 30.5% of all patients stopping treatment with pirfenidone at some time during the Correspondence
observation period, nor did we set FVC as 0 in case a subject died (as had been done previously). Our patients were also older and more advanced compared with patients in previous randomized controlled trials. Of the patients in our trial, 23.4% were treated with bronchodilators before the onset of pirfenidone treatment, and no patient received pirfenidone along with bronchodilators. In line with such reasoning, the addition of age, use of bronchodilators, and sex did not improve the fit of the GLM model in the study and the control cohort. Second, an intraindividual, annual FVC decline greater than 10%, alternatively also greater than 5%, was used for stratification, as a decline of 5–10% or more is accepted as clinically meaningful (11, 12). Employing this approach, patients with a clear progression showed an even more favorable course under pirfenidone and actually improved. Such behavior reminds us of the treatment effect of imatinib in patients with pulmonary arterial hypertension, in whom the highest treatment effect was encountered in the subgroup of patients with the highest pulmonary vascular resistance values and, hence, the most active vascular remodeling processes (13). One may speculate that matrix deposition and dissolution take place at a much higher pace in progressive IPF. Under such conditions, blockade or a reduction of matrix production and deposition may actually result in matrix removal, provided abundant 111
CORRESPONDENCE trend FVC (yearly change) >0.3
2.0
0.1
1.8 p=0.0715
post
FVC/FVCtime=0
1.6 1.4
−0.05 −0.1
1.2 1.0 −0.3
0.8 0.6 0.4
